We have been working since 1985 to localize the putative gene for Tourette's syndrome (TS) using pedigree linkage analysis. While clinical features particular toTS, heterogeneity of illness and uncertainties regarding inheritance pattern represent potential pitfalls of our approach, we anticipate that successful localization of the disease gene by linkage analysis can and will be accomplished. This effort now requires ongoing clinical evaluations of large kindreds affected by TS in order to: 1) expand our clinical database, 2) refine the accuracy of diagnostic assignment, including associated behavioral disturbances (i.e., obsessive compulsive and attentional disorders), and 3) carry out psychometric standardization of a new rating scale for TS. We also plan to expand our computerized registry of TS pedigrees which should prove valuable once a linked marker is identified to rule out genetic heterogeneity, assess linkage dysequilibrium, and determine recombination frequency. In addition, a prospective assessment of family members at high risk for TS will address nongenetic factors (e.g., life stresses, exposure to certain medications) that may influence the clinical expression of the illness. Localization of the gene for TS will strengthen clinical diagnosis, improve genetic counseling, elucidate pathophysiology and provide clues for more rational therapies.